Infertility is a well-documented complication following MOPP (Nitrogen Mustard, Vincristine, Procarbazine, Prednisone) chemotherapy in Hodgkin's patients, and is a specific example of the effects of many antineoplastic drugs on the germinal epithelium. Clinical evaluations demonstrate aspermia is at least partly responsible; laboratory investigations suggest that very early embryonic death (dominant lethality) may also contribute. The proposed research has, as its specific aims, to determine the mutagenicity and cytotoxicity of the drugs used in MOPP therapy, individually and in combination, when administered in a single dose or multiple injections. The sensitivity of each spermatogenic stage will be determined with emphasis on the stem cell speratogonia. The manifestation of induced damage in the zygote will be determined. An in vivo - in vitro murine assay for dominant lethality will be used wherein drugtreated males are mated to untreated females and the offspring cultured from the 2-cell stage to an early post-implantation stage. The developmental capacity of embryos sired by treated males compared to embryos sired by untreated males is used as the index of mutagenicity. This assay, unlike those in vivo, readily discriminates preimplantation embryo death from an inability to fertilize. In describing the mutagenic and cytotoxic activities of these drugs, their additivity or synergy, the effect of their order of administration, and the possible recovery from drug-induced damage, it is anticipated that these studies will contribute to the design of a protocol for estimationg genetic risk by such agents and methods of reducing their hazards without compromising their therapeutic effectiveness.